RBC alloimmunization may occur through exposure to non- self RBC antigens during transfusion therapy or during fetal/maternal bleeds in pregnancy or delivery. These antibodies can be dangerous from the perspective that alloimmunized patients are at increased risk of having hemolytic transfusion reactions following subsequent transfusions. They may also be dangerous; however, to fetuses whose RBCs express cognate antigens. Hemolytic disease of the fetus and newborn (HDFN) occurs in more than 1/600 pregnancies and may be deadly. Although naturally occurring antibodies against A or B antigens may cause mild HDFN, severe HDFN is caused predominantly by antibodies directed against antigens such as D or Kell. The only therapy that exists to prevent alloimmunization during pregnancy is polyclonal anti-D, and its mechanism(s) of action are unclear. There are currently no therapies to prevent immunization to non-D antigens, nor are there targeted therapies to minimize the dangers of existing maternal alloantibodies. This therapeutic gap exists in part due to technical and ethical limitations of human studies, most of which have been limited to observation/correlation studies between antibody specificity, titer, and fetal outcome. Herein, we present a novel murine model of pregnancy (and transfusion) induced anti-KEL RBC alloimmunization, in which anti-KEL crosses the placenta, binds to KEL positive fetal RBCs, and appears detrimental to pups. Progressively smaller litters are produced by immunized mothers in successive pregnancies compared to virgin non-immunized control females. Central Hypothesis: Maternal KEL alloantibodies are detrimental to KEL positive pups through 1) binding and subsequent clearance of fetal RBCs and/or 2) suppression of fetal erythropoiesis. Maternal de novo generation of anti-KEL will be prevented by IM administration of polyclonal (but not monoclonal) KELGam through removal of KEL positive fetal RBCs and/or through masking/loss of the KEL antigen on these RBCs. Specific Aim 1: Functional Characterization of Anti-KEL Generated Through Transfusion Versus That Generated Through Pregnancy Specific Aim 2: Assessment of the Abilities of Polyclonal KELGam and Monoclonal Anti-KEL on Fetal RBCs and on the Prevention of Maternal RBC Alloimmunization during Pregnancy Public Health Significance/Long Term Goals: This proposal is relevant to public health in that it describes the first animal model of RBC alloimmunization induced by pregnancy which results in fetal demise, capitalizing on the strengths of an animal model to explore questions that have not (and cannot) be answered through observational human studies. The ultimate long term goal of this work is to diminish the morbidity/mortality of maternal RBC alloimmunization in fetuses and newborns alike. PUBLIC HEALTH RELEVANCE: Maternal anti-RBC antibodies, which may develop following exposure to foreign RBC antigens during transfusion or feto/maternal bleeds during pregnancy, may be deadly to fetuses expressing a cognate antigen. Hemolytic disease of the fetus and newborn (HDFN) occurs in more than 1/600 pregnancies, and with the exception of polyclonal anti-D (RhoGam) there are no targeted therapies to prevent alloimmunization. This proposal is relevant to public health in that it describes the first animal model of RBC alloimmunization induced by pregnancy which results in fetal demise, capitalizing on the strengths of an animal model to explore questions that have not (and cannot) be answered through observational human studies; the ultimate long term goal of this work is to diminish the morbidity/mortality of maternal RBC alloimmunization in fetuses and newborns alike.